The pRb tumor suppressor pathway is inactivated in most human cancers. In an attempt to model human cancers, we have inactivated this pathway tissue-specifically in the mouse by transgenic expression of T121, a truncated SV40 T antigen that binds and inactivates pRb and related proteins p107 and p130. Previously we showed that inactivation of the pRb proteins in choroid plexus epithelium (CPE) induces aberrant cell proliferation and p53-dependent apoptosis. Thus, pRb inactivation initiates tumorigenesis and sets up subsequent tumor dynamics. Aggressive tumor growth occurs upon p53 inactivation due in part to reduced apoptosis. During the last funding period, we analyzed the p53 tumor suppression pathway and have shown that p53 loss also facilitates progression by an as yet unknown mechanism. We have also extended these studies to examine additional epithelial cell types, including prostate (PE) and mammary (ME). In both cases inactivation of the pRb pathway leads to a similar induction of aberrant proliferation and apoptosis. However, while most apoptosis is mediated by p53 in CPE and ME it is mediated by PTEN in PE, indicating important mechanistic differences among cell types. In all cases, these responses predispose to adenocarcinoma, establishing tumor models characteristic of the human diseases. This proposal aims to integrate studies on cancer mechanisms in these epithelial cell types using genetically engineered mice (GEM). Our goal is to understand the mechanisms by which these events contribute to cancer development, thereby exploring the extent of cell specificity and characterizing the preclinical models we have established. The specific aims are to: (1) Define the p53-mediated apoptosis pathway(s) in tumor suppression. (2) Examine the mechanism(s) by which p53 and PTEN loss contribute to tumor progression in CPE, ME and PE. (3) Generate a pan-epithelial inducible system to inactivate the pRb pathway.